Monitoring Temperature-Sensitive Cargo with Automated Generation of Regulatory Qualification

ABSTRACT

Disclosed is a process of determining, at a point during shipment, whether the solid phase refrigerant in a shipment is sufficient to preserve the shipment cargo, which is blood or other biological products, for the remaining shipment period, by: monitoring the temperatures encountered to said point and estimating the temperatures likely to be encountered during the remaining shipment period; determining the likelihood that the remaining refrigerant can maintain the shipment cargo within a specified temperature range during the remaining shipment period; and if the risk that the remaining refrigerant cannot maintain the shipment cargo within said range during the remaining shipment period is above a cut-off level, then taking action to preserve the value of the cargo.

FIELD OF THE INVENTION

The invention relates to monitoring shipment of blood and othertemperature-sensitive biological products.

BACKGROUND OF THE INVENTION

Shipment of blood and perishable biological materials is problematicbecause of the short effective life of these products, and their highvalue. In general, insulated containers in combination withtemperature-control agents, such as refrigerant materials, are widelyused as a cost-effective system to maintain the temperature of shippedproducts at selected temperature ranges, including refrigeration (2-8°C.); room temperature (20-30° C.); or frozen (below 0° C.). Thetemperature-control agents are generally phase change materials, ice,gel packs, or dry ice.

Phase change materials are materials which may be repeatedly convertedbetween solid and liquid phases and utilize their latent heats of fusionto absorb, store and release energy to heat or cool during such phaseconversions. In contrast to a material that absorbs and releases energyessentially uniformly over a broad temperature range, a phase changematerial absorbs and releases a large quantity in the vicinity of itsmelting/freezing point, thus facilitating temperature maintenance nearthe melting/freezing point.

Passive refrigerant systems utilizing insulated containers and phasechange materials (and/or ice, gel packs, or dry ice) provide sufficientrefrigeration for relatively short shipping periods, where, as anadditional condition, the ambient temperature does not vary greatly fromthe internal temperature for extended periods. As shipment times areoften longer than the period where ice in an insulated container willmelt completely, refrigerant systems using combinations of phase changematerials, gel packs and insulated containers are commonplace forshipment of temperature-sensitive products. See, e.g., U.S. Pat. Nos.7,849,708; 7,294,374 and 8,375,730 (all of which are incorporated byreference). Other systems of insulated containers and phase changematerials can be used to extend the time that products within aremaintained at room temperatures or at temperatures below freezing (andthe latter systems may also include ice or gel packs or dry ice, asappropriate), so as to match the shipment period and the shipmentconditions (most importantly, the ambient temperature). See U.S. Pat.No. 8,375,730 (incorporated by reference).

One issue which has not been addressed is how to best retain the valueof blood and other perishable products during shipment. Units of wholeblood and red blood cells are kept refrigerated at (1-6° C.), withmaximum permitted storage periods (shelf lives) of 35 and 42 daysrespectively. Platelets are typically pooled before transfusion and havea shelf life of five days—or three days, assuming it takes two daysfollowing collection to complete their testing. Platelets are stored atroom temperature (22.2° C.) and must be rocked. If there are significanttemperature excursions during shipment of blood and biological products,it renders these products unacceptable for medical uses and thusvalueless.

Thus for shipping blood and biological products with passive refrigerantsystems, sufficient refrigerant must always be present to maintain therequired storage temperature. The ambient temperature significantlyaffects the conversion rate of the refrigerant, and thus the time bloodand biological products can be in shipment before an unacceptabletemperature excursion takes place (which is one where the temperature isabove a threshold for a given period; such that the higher thetemperature, the shorter the given period before spoilage).

Time in shipment can only be estimated, as there are many sources ofdelay during shipment, both conventional and unexpected. Also, thetemperature during shipment can only be estimated based on expectedweather conditions and knowledge of shipment mode internal temperaturesand warehouse temperatures. If a shipment of blood or biologicalproducts is delayed, and/or the temperature varies beyond expectationduring shipment for more than a prescribed period, it is important todetermine how much time is left before a sufficient quantity of therefrigerant is converted to cause an unacceptable temperature excursion.For blood or biological products, it is also important to haveverification of appropriate shipping conditions (esp. temperature) forregulatory compliance purposes, for both the recipient and the shipper.

SUMMARY

The invention relates to a first embodiment for preservation of value inbiological products and other perishable items, by using a logger oftime/temperature (or real time RF transmission of time/temperature) soas to allow determination of the amount of refrigerant remaining, duringshipping of the products. The logger can be embedded in or attached tothe shipping container (or its packaging), and preferably has multiplesensors for temperature (and more preferably, also for humidity) whichextend into the shipment carton to more accurately record thetemperature and humidity in the area of the cargo.

The invention also relates to a second embodiment for logging oftemperatures and times of exposure to different temperatures. The secondembodiment preferably carries the time/temperature log in both itsinternal memory (for reading by downloading to a device) and in anencoded displayed form, like a 1D or 2D bar code. The 1D or 2D bar codecan be scanned with a CCD (cell phone camera, tablet camera or otherCCD) and decoded to provide all logged information. The encoding of thedisplay is preferably done with commonly available and readableencryption, so it can be readily decoded by the user of the shippedproduct.

The invention also relates to a third embodiment for automatedqualification of biological products and other perishable items ormaterial shipped. In this third embodiment, a time/temperature loggershipped with the materials has a certificate coded to the materials andoperatively associated with the logger which carries an authenticationof the time/temperature log, which can be used in certifying that thematerials shipped are suitable for intended use (from a time/temperatureexposure standpoint). Preferably, this certification carries allinformation needed for an NTIS (National Technical Information Service),US Food and Drug Administration (FDA), World Health Organization (WHO)or other regulatory or advisory compliant certification. If socompliant, it can be used to satisfy requirements in the medical, bloodbanking, biotech and pharma industries for the shipment certified. Thelogger can also have other features useful for loggingtime/temperature/humidity and alerting an operator about deviations, andcertifying the shipment quality, as described further in the DetailedDescription.

The first embodiment is accomplished by monitoring of the shippingsystem temperatures during shipment and the period of time at varioustemperatures, and from that information and the characteristics of theshipping system, deriving the amount of refrigerant remaining. Then, thetemperatures (and preferably the humidity), and the time period at suchtemperatures (and preferably at each such humidity) to be encounteredare predicted (from a database of logged shipments or from forecasts)and a determination is made of how long the remaining refrigerant cansustain the products within the required temperature range. Thedetermination of how long the remaining refrigerant can so sustain theproducts depends on determining the relationship between the externalpredicted temperatures and humidity and the time at each suchtemperature or humidity, and the temperature within the shippingcontainer which houses the product and the time the product is at suchtemperature. The temperature within the shipping container (when at aconstant ambient temperature) will change as more refrigerant isconsumed, until finally reaching equilibrium with the ambienttemperature. A larger temperature gradient between interior and ambientwill, of course, result in more rapid consumption of the refrigerant, aswill longer time periods at higher temperatures and higher humidity.

After the remaining refrigerant quantity is determined, if the level isunsuitable or unsafe for the remaining shipment period, action can betaken, including moving the shipment to a faster transportation mode,instructing the shipper to add refrigerant, or diverting the shipment ormoving the container (if it is in a warehouse) to atemperature-controlled environment (e.g., a refrigerated unit or arefrigerated cargo hold in a train, airplane or truck). The action takenmight also be diverting the shipment to a nearby facility where thebiological products can be used on site more immediately than originallyplanned. The monitoring and prediction described herein therefore allowsone to take action to retain the value of biological products as therefrigerant level drops and shortens the effective life of the products.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow diagram showing the steps in determining whether theproduct being shipped should be diverted, have refrigerant added, or bemoved to a refrigerated area, where the assumed temperature range overthe entire remaining shipment period T_(R) is determined then applied.Where continued monitoring shows temperature excursions outside ofexpected ambient temperature range, the determination needs to berepeated based on the updated information.

FIG. 2 is a flow diagram showing the steps in determining whether theproduct being shipped needs to be diverted, have refrigerant added, orbe moved to a refrigerated area, where the assumed temperature rangeover a plurality of segments of the remaining shipment period T_(R) isdetermined then applied. Where continued monitoring shows temperatureexcursions outside of expected ambient temperature range, thedetermination needs to be repeated based on the updated information

FIG. 3 depicts four LED indicators on a logger, with two for indicatinghigh temperatures (the left most indicators) and two for lowtemperatures (the right most indicators). One or both of each of thehigh temperature and low temperature indictors can be on or off.

FIG. 4 depicts a logger (30) for attachment to or embedding in ashipping carton (which can be an RFID logger); having multiple sensors(the arrows) for temperature and/or humidity designed to extend into theshipment carton to near the cargo (40).

DETAILED DESCRIPTION Using the Embodiments

In the invention, first a suitable container and refrigerant system forproducts requiring maintenance within a specified range of temperaturesduring shipment (including blood, blood products and other biologicalproducts, for example, cells, tissues, organs, microbes, microbialspores, yeast, plants and plant materials) is selected based onestimated shipping time and temperatures expected to be encounteredduring shipping. The process requires a prediction of the maximum periodof shipment, and the predicted ambient temperature ranges and time ofexposure thereto for the system during the maximum period of shipment.Alternatively, instead of predicting ambient temperature ranges for thesystem and time of exposure thereto, a postulated worst case scenariofor ambient temperatures (winter and summer) and time of exposurethereto can be used. The lowest-cost system likely to accomplish theobjective of preserving the cargo can be selected, as the monitoring ofthe shipment provides for taking corrective action if the system mightfail to be adequate for the entire shipment period.

The “ambient temperature” of concern is the ambient temperature for thesystem—not the environmental ambient temperature. The ambienttemperature for the system is the temperature inside the cargo area ofthe shipment mode (i.e., inside a truck-trailer, a train or an airplanecargo hold) or in a warehouse while in transit, as this temperature iswhat affects the conversion rate of the refrigerant. Of course, theenvironmental ambient temperature and humidity will affect the ambienttemperature of the cargo area, unless the cargo area is activelytemperature-controlled. The environmental ambient temperature andhumidity will change as the system moves to its destination throughenvironmental temperature fluctuations, thereby causing the ambienttemperature in the cargo area to also fluctuate (again, unless it istemperature-controlled).

The system selected for shipping can include some combination ofinsulated container(s), phase change materials, and other temperaturecontrol agents such as ice, gel packs or dry ice. The selection can bedone by an algorithm which, based on heat transfer characteristics ofthe system containers and melting characteristics of thetemperature-control agents, identifies a system which is likely able tomaintain the product temperature within the required range under thepredicted conditions for the shipment period, as described in U.S. Pat.No. 8,375,730 (incorporated by reference).

Either experimentation, or derivation from the properties of the systemcomponents, can be used to establish a database for a variety ofpackaging and temperature-control systems. The database provides thelength of time each member system in the database can maintain productswithin a specified range of temperatures, when the member system isexposed to specified ranges of ambient temperatures (and humidity) forspecified time periods. The database may also provide historicinformation on environmental ambient temperature and humidity alongdifferent shipment routes, in different seasons. The database can beused in deriving the predicted temperatures ranges the system will beexposed to during shipment to a specified location over a predictedshipment period with a particular system, or these predicted ranges andexposure times can be entered by the operator. As noted, the system isto be monitored during shipment to ascertain the cargo ambienttemperature and time of exposure thereto, and preferably, there is alsomonitoring of the system's internal temperature during shipment—in orderto verify the predictions, supplement the database, and provideprotection for the products in case of temperature excursions exceedingspecified periods. A logger which can perform such ambient temperatureand/or cargo ambient temperature logging is described in the DetailedDescription below.

As noted above, an alternative to predicting ambient temperatures andthe shipment period is to establish worst case scenarios—i.e., thepredicted boundaries of the temperature range(s) in summer and winter,and the maximum predicted period of shipment/exposure based ondestination and mode of shipment selected. Then, a system is selectedwhich will maintain the products within the required temperature rangeunder these conditions; and it will necessarily also do so undergenerally-encountered shipping conditions. Again, monitoring of theambient and system internal temperatures during shipment can be used inconjunction with such predictions to ascertain whether the productsremain in an acceptable temperature range during shipment.

With respect to shipment of blood from donors, for direct donationand/or for processing into blood products, currently, Fresenius HemoCare(Redmond, Wash., USA) offers two cooling and transport systems for bloodbags: Compocool, and a more recent version, Compocool II™/Compocool WB™,in which the butane-1,4-diol cooling unit is placed in an insulatedcrate. Additionally, Sebra/Haemonetics (Tucson, Ariz., USA) offersbutane-1,4-diol-filled transparent pouches (ThermaSure), developed forthe transport of platelet concentrates and blood units at 22±2° C. Oneof more of these cooling and transport systems, or other suitable bloodcooling and transport systems (including those in U.S. Pat. Nos.8,192,924; 8,349,552, both incorporated by reference), can be thecooling system selected in the method described herein for shipping ofblood bags. In such case, the cooling and transport system (with theblood bags) would be placed into an insulated container, which may haveadditional temperature control agents.

Blood, organs for donation and other biological products must staywithin a confined temperature range to be suitable for recipients. Theselection method and monitoring described herein is particularlywell-suited to selection of systems for blood and blood productshipment.

Following shipment, the time-temperature-humidity log in the loggermemory, or the displayed encoded log in the second embodiment, and/orthe automated certificate in the third embodiment, provide informationabout the suitability of the products based on temperatures theyencountered and the times of such exposure. The products shipped canalso be evaluated, assayed or tested following shipment to determinetheir donor compatibility or otherwise, and their suitability for invivo or medical use.

The certification or verification of the cargo's integrity forregulatory purposes, which is done using the third embodiment above, canalso be accomplished with conventional systems where a certificate isgenerated after shipment from the logger data, or with one or more ofthe logger and/or sensor embodiments described below.

The second and third embodiments of the invention described above (thebar-coded log display and the automated qualification certificate), ifpresent, will both increase the practicality of diverting the shipmentto a different location than originally planned, as the new location hasa displayed (encoded) time/temperature (and optionally, humidity) log,which can be readily scanned and decoded, as well as a certificationthat the product it receives is qualified, from a regulatory standpoint,for the end use. The automated qualification certificate andtime-temperature log display also shows the recipient if the attempts topreserve the shipment were successful (i.e., if the temperature stayedwithin prescribed limits for specified times notwithstanding theshipment's diversion).

Implementation of the Shipment System

Monitoring temperatures over time periods during shipment can be donewith one of several commercial systems, including the Escort iMini™, theREDi Wireless™, and the Wireless Mini™, all made by Escort Dataloggers,Inc. (Buchanan, Va.). Data from these monitors can be viewed and plottedusing the ESCORT Chartreader™. For the real time monitoring suitable foruse with the systems herein (though not required for most systems), boththe REDi Wireless™ and the Wireless Mini™ are suitable, as the data canbe read or downloaded remotely.

To carry out the second embodiment without real time monitoring using RFor wireless transmission, the time-temperature-humidity loggerpreferably identifies the materials shipped (for example, using a barcode), and also preferably has a coded display of thetime-temperature-humidity (again, preferably a bar code) which can bescanned and readily decoded. The coded display in this embodiment can beGS 1 or other reduced space symbology (RSS) encoding, as this encodingcan display more data in a smaller display, and thetime-temperature-humidity log could entail a large amount of data.

For the third embodiment, the time/temperature logger must internallycarry data for a certificate, and preferably, the logger will carry thedata or a certificate itself in an all-device readable file format (likePdf, Excel, Text or other widely-used format), and more preferably thelogger can be directly plugged into a device port for reading the dataor certificate (e.g. a USB port, where the logger has a USB male end, oranother type of port, if the logger has another compatibility). With aUSB or other port compatibility on the logger and an internal fileproviding a record of the time-temperature-humidity data, or thecertificate, it can be plugged into a USB or other port of a smart phoneor device that includes an internal reader program for the file format,and the data or certificate can then be read directly. More preferably,the logger will also include other features including for exampleindicators as shown in FIG. 3 and additional sensors as shown in FIG. 4,and also as described in the section below “Logger and SensorEmbodiments.”

In all embodiments, the time/temperature logger is used in an algorithmto predict the amount of refrigerant remaining, and if the prediction ofremaining shipment time and temperature determines that the refrigerantis likely to be insufficient to maintain the required temperature of thecargo, the recommendation is for action to be taken to preserve thevalue of the cargo. Over the course of shipment, the ambient temperature(i.e., the temperature the shipping container experiences) varies overtime. The simplest case to ensure that the packaging system selected forshipment will comply with the time/temperature range restrictions forthe products it carries, is to assume the ambient temperature range canbe at the highest ambient summer temperature or at the lowest ambientwinter temperature for the entire shipment period. Monitoring atselected points or intervals en route of the temperature and humidityencountered during shipment allows verification of the predictedconditions and allows determining the amount of refrigerant remaining,and allows tracking of product quality or expiration. The data loggedcan also be used to refine the database of predicted temperature overthe route, for the season the shipment took place—thereby allowingcontinuous updating of such a predicted temperature database, to make itmore reliable.

Determining the quality/expiration properties of shipped goods can beaccomplished using loggers associated with particular shipment systems.In general, the logger can be inputted with a correlation or functionwhich allows the computation of quality or expiration of a particularcargo based on a known or experimentally determined correlationestablished between time of exposure and temperature, for such cargo.Alternatively, the data for use in such correlation or function can bedownloaded from the logger memory, and determined by another computingdevice. A number of functions exist for modeling degradationrelationships including Arrhenius, Weibull, Eyring or Belehradek typefunctions, see U.S. Pat. No. 7,392,150, incorporated by reference, aswell as Newton's law of cooling. It is also possible to run degradationsimulations, using, e.g., bacteria cells instead of human biologicalcells.

In applying the Arrhenius equation to determine aging speed of atemperature-sensitive product (e.g. ageingspeed=1/e^((a+b(temperature))), besides a knowledge of the good-specificconstants, which are “a” and “b,” a knowledge of the temperature overtime is needed. This calculation provides a more accurate way to predictcargo quality and expiration than simply to monitor temperature and timevalues. If the algorithm result is monitored continuously (or at short,equal, intervals) during the monitoring period, then the qualitydetermination is more reliable. The logger embodiments described in thesection below “Logger and Sensor Embodiments” can run such algorithmsand log the results, which can then either be transmitted wirelessly oruploaded to another device, also as described below.

Design of Shipment System

The first step in shipment of highly perishable goods is to select asuitable shipment system. The system can be selected based on lowestcost likely to accomplish the objective, as the monitoring of theshipment permits taking corrective action if the system selected provesinadequate. At various points or intervals during shipment, adetermination of whether the remaining refrigerant is adequate can bemade based on projecting the simplest case scenario (where one assumesthe temperature range during shipment is either the highest likely orthe lowest likely temperature) over the entire remaining shipmentperiod.

The simplest case scenario can be segmented to represent exposure timesto different ambient temperature ranges likely to be encountered enroute. The total of these ranges and exposure times represent the rangesencountered during the shipment period and/or the remaining shipmentperiod. Segmenting in this manner provides a more reliable prediction ofthe temperatures to be encountered during shipment. Again, at selectedpoints during shipment, one can apply the segmented scenario to theremaining shipment period (designated S_(R) in FIGS. 1 and 2), todetermine if the remaining refrigerant is sufficient to sustain therequired temperature during S_(R).

As an example of segmenting during S_(R): the system may begin itsjourney in a truck trailer without temperature control, then move to atemperature-controlled warehouse, then back to an uncontrolled trucktrailer to finish its journey to the destination. If S_(R) isdetermined, for example, after the truck trailer leaves the cargo in thetemperature-controlled warehouse (before the final leg of the trip),then if s^(TT) is the time remaining for shipment on a truck trailer,and if s^(W) is the time the cargo is to remain in the warehouse, thenS_(R)=s^(TT)+s^(W). The prediction of ambient temperature range wouldthen only be applied during s^(TT) in determining whether the remainingrefrigerant could sustain the cargo, as the ambient temperature durings^(W) would be known.

As experience (actual data) is collected by loggers to determine theactual range of the ambient temperatures encountered, and the time ofexposure to different temperature ranges on different shipment routesduring different seasons, the temperature model can be modified, so thatinstead of applying the expected summer and winter high and lowtemperature (based on publicly available information) across S_(R),values of summer and winter high and low temperatures closer to thoselikely to be experienced are substituted, and used with the expectedtimes of exposure to these temperature ranges to determine remainingrefrigerant over S_(R). In the preceding scenario, during s^(TT), if thetemperature range applied in the model is based on experience ratherthan worst case, it will more reliably predict the amount oftemperature-control agent likely to be consumed during s^(TT).

The properties of shipment systems related to their ability to maintainthe required inner temperature over the predicted ambient temperatures(especially heat transfer) are preferably tested or otherwise determinedexperimentally, and then the information is stored in a database. Onetesting method is to expose a series of systems to high temperatures anddetermine the melting time(s) for temperature-control agents inside.Another method of selecting systems is by derivation of expectedtemperature-control agent melting time(s) from the properties of thesystem's containers and temperature-control agents, at the predictedambient temperature and time of exposure thereto.

In a preferred embodiment, during shipment, after monitoring the ambienttemperatures and logging the results, a computer program (which can bein the logger internal programs) runs an algorithm to determine theremaining effective life of the temperature control agent(s), based onthe properties of the shipment system, the temperature control agents,the ambient temperatures experienced and the ambient temperaturesexpected. The properties of the shipment system and the temperaturecontrol agents include the heat transfer characteristics of differentsystems (i.e., the heat transfer characteristics of both the temperaturecontrol agents and the container(s) in a system), and also the meltingcharacteristics of the temperature-control agents. During shipment,therefore, the algorithm derives melt times and inner temperatures ofdifferent systems, and a logger can include enough indicators (see FIG.3) to display (by coding) both whether the products on board arespoiled/unsafe for use, and whether the system can maintain the requiredproduct temperature for the remaining shipment period at the expectedtemperatures.

The situation where the remaining shipment period is segmented is shownin FIG. 2; and the non-segmented case is in FIG. 1. The ambienttemperature applied by the algorithm can be the simplest case projection(a range from expected summer highs to winter low temperatures over theshipment route for the shipment period) or the segmented ranges andtheir respective times experienced. The ambient temperatures in thedatabase can be updated and supplemented based on those actuallyexperienced by systems, or, updated based on derived ambienttemperatures resulting from the environmental ambient temperatureslogged or predicted. The algorithm in a logger can also indicate thestandard deviations in temperatures and shipment times, along differentpoints in the route. This can allow an operator receiving informationfrom the logger to determine the risk of unacceptable temperatureexcursions during the remainder of the shipment, and based on thatcalculation of risk, instruct action to preserve the cargo (as indicatedin FIGS. 1 and 2). Again, the information can be received wirelessly orby downloading it from the logger.

A database of environmental temperatures along shipment routes (fromwhich ambient temperature can be derived) can be established bycompiling the historical temperature records for the route, or by actualmonitoring, or by a combination of historical data and actualmonitoring. In providing for the widest safety margin, one woulddetermine the highest summer temperatures and the lowest wintertemperatures ever recorded, and then derive ambient expected temperaturefrom those extremes—preferably with a standard deviation for each. Theexpected ambient temperatures (from the database) can be in a computeror device for processing, and also could be loaded into a logger memoryfor processing when it is to determine if the remaining refrigerant isadequate.

On the other hand, if a shipper can warranty certain ranges of ambienttemperatures for the remaining shipment period (i.e., climate controlledshipment and warehousing, from start to finish), there is no need toestimate the expected environmental ambient temperature. Where there isactive monitoring of temperature and humidity as described herein, thekey to preservation of the product shipped at a point during shipment isto ensure there will be no delays during the remaining shipmentperiod—which the shipper may also warranty. If delays are expected, orif the shipper will not provide a warranty, action can be taken topreserve the cargo (as indicated in FIGS. 1 and 2). In the event of suchwarranty, however, the logger is still needed or useful to therecipient, as it verifies and can be used to certify the quality of theproducts shipped.

As noted, the time/temperature and time/humidity data logged fromshipments can be added to the database, which is preferably doneautomatically. As the database expands, the predictions of thetemperature ranges during various segments of shipment along routeswhere more data has been accumulated should become more reliable anddeviations should narrow. The loggers with the shipments thus allowexpanding and verifying a database, and generating a more reliabledetermination of which system (lowest cost) to select, and further, ofwhen action is needed to preserve the shipment.

The temperature, humidity (and optionally related conditions that mayaffect temperature-control agent melting like atmospheric pressure)should be collected from the logger at multiple points during shipment.These datapoints can be used to construct a cold chain map. The map ispreferably plotted at different times of the year to form a series ofseason-specific cold chain maps. These season-specific cold-chain mapscan be used to derive a more accurate prediction of the temperatures thesystem would be likely to experience during any particular shipmentsegment.

The data on temperature during shipment can be collected usingdatalogging devices which are analyzed after or during shipment, or withthe devices which transmit time/temperature data to a monitoring station(using RF transmission) throughout shipment. Both types of devices areavailable from Escort Data Loggers, Inc., Buchanan, Va. Actualmonitoring or logging of temperature changes may be needed for customerassurance, or to meet the FDA GMP requirements, if the products aresubject to FDA jurisdiction as are, for example, pharmaceuticals,biological products or blood products. The loggers described hereintrack and log the temperature automatically during shipment, and thetemperature log is also automatically documented—which is necessary formany FDA regulated products and where documentation is part of thestandard operating procedures (SOPs) for products.

A database also includes heat transfer characteristics of the systemconstituents, including the containers. The materials forming thecontainers are typically conventional materials used in fabricatingportable coolers, e.g., expanded polystyrene or polyethylene, because oftheir insulating properties. The database also includes meltingcharacteristics of a variety of phase-change materials and coolantswhich can be included in the packaging, as well as meltingcharacteristics of a number of combinations of packaging and phasechange materials and/or coolants. The algorithm used to determinewhether the system can maintain the cargo for the remainder of theshipment period S_(R), can display several alternative scenario based onexpectations, and an operator can select one which best satisfies theneeds in a particular case:

-   -   1. Determine if the system can meet the worst case temperature        range for S_(R) (FIG. 1).    -   2. Determine if the system can meet the time-segmented        temperature ranges for S_(R) (FIG. 2).    -   3. Determine if the system can meet the worst case or        time-segmented temperature ranges for S_(R), where the        temperature ranges are based on historic data and/or weather        forecasts for the shipping route.    -   4. Determine if the system can meet the worst case or        time-segmented temperature ranges for S_(R), where the        temperature ranges are based on historic data and/or weather        forecasts for the shipping route and/or on data collected during        shipment on the route.    -   5. For systems meeting the criterion in any of scenarios 1 to 4        above, determine the risk of cargo destruction due to        temperature excursions/refrigerant conversion for each scenario;        and    -   6. Where risk is above a cut-off level (where the cut-off level        is based on cargo value) select a system (likely higher cost)        which is more likely to preserve cargo value; or, be prepared to        respond en route (based on the results of monitoring with the        logger) with action to preserve the cargo value.

En Route Response to Unacceptable Cargo Risk

Having selected a shipping system based on the criteria above, as notedin factor 6 above, monitoring of time/temperature allows responses enroute to preserve the cargo value. The cut-off level for the risk level(in factor 6) can be pre-set, and would be lower where cargo value washigher. The cut-off level could also be graded depending on the actionto be taken, and its feasibility. For example, it may not possible to“add refrigerant” to the shipping system, in locations or on routeswhere no suitable refrigerant (typically a phase change material) isreadily available. It may also not be possible to divert the shipment tohave the cargo used within its remaining effective life. No proximatefacility may be willing to purchase/take the cargo. Thus the action tobe taken in such cases could only be “expedite shipment,” which islikely the most costly alternative to preserve the cargo value. Suchrelative costs can be taken into account by setting or re-setting thebasic risk cut-off level—i.e., the risk can be re-set to a higher levelif only higher-cost alternatives are available, meaning a system whichhas a prospect for longer cargo preservation is preferred. Of course ifthe cost of action is greater than the value of the cargo to bepreserved, that can be built into the calculation as a limitation onfurther action. It is also possible to have communication with thecustomer about the course of action to be pursued, and to obtain theirdirect approval for any action to be taken. In any event, monitoring bythe logger during shipment allows the risk to the cargo during theremainder of the shipment to be more accurately assessed—as its exposureto such point would be better quantified.

The different courses of action to preserve the cargo value and theircosts can be programmed as an algorithm, and the lowest cost alternativecan be determined by the algorithm. Again, this could be performed bythe logger with an internal function, if desired.

Logger, Certificate and Sensor Embodiments

Monitoring systems available from Escort Data Loggers, Inc. allowtransmitting data regarding temperature, and also pressure, relativehumidity, and CO₂ levels, using RF, other wireless modes or WiFi. Othermonitoring systems available from Escort Data Loggers, Inc. keep aninternal record of temperature and time of exposure in the logger devicememory. If a GPS system is included with the device, it allows locatingthe system at the time data is recorded or sent/received. Indicatorswhich can be monitored indicate temperature excursions, and arepreferred where maintaining product temperature is critical; i.e., forblood or other biological products. The data logged internally ontime/temperature or transmitted is preferably also recorded andpreserved on a database, which is preferably web-accessible. As noted,this database and monitoring system can be used to verify or refutepredicted temperatures, to establish or supplement a cold chain mapalong different shipment routes, and most importantly, to establish theeffective amount of the remaining refrigerant and determine if it willbe effective over the expected remaining shipment time.

The logger system described below and shown in FIG. 3 is a suitablelower-cost alternative to the foregoing systems which transmit data.This logger has four or more LEDs which indicate time/temperature, andtherefore status of the cargo. One system of coding the four LEDs is tosplit them so that two which signal in one color indicate hightemperature and two which signal in another color indicate lowtemperature. Then, temperatures above an uppermost limit for a specifiedperiod can be indicated by activating two high signals, and temperaturesabove a limit lower than the uppermost for a specified period can beindicated by activating one of the high signals only. Similarly,temperatures below a lowermost limit for a specified period can beindicated by activating two low signals, and temperatures below a limithigher than the lowermost for a specified period can be indicated byactivating one of the low signals only.

The FIG. 3 logger is shown with only one left-hand indicator on,indicating the temperature was above a primary high threshold for aspecified period. The FIG. 3 logger is also shown with only oneright-hand indicator on, indicating the temperature was below a primarylow threshold for a specified period as well. Such indicator arrangementas in FIG. 3 can provide a quick visual indication of the cargo status,and where the signals are designed to remain on, the indication of cargostatus can be viewed at the destination. A number of patents discussloggers which keep signals on without consuming excess battery power,and are hereby incorporated by reference: e.g., U.S. Pat. No. 7,392,150refers to a low-energy consuming LCD for signal display (col. 4, line37).

The preferred logger also includes all software needed to generate acertificate of time/temperature (preferably regulatory compliant) duringshipment in pdf, excel, text or other readable format. The preferredlogger can be connected to a USB port of a device, and the certificatecan be read with reader software on the device. Thus, it can be read bytablets, smart-phones and other hand-held or portable computing deviceswhich recipients, warehouses, shippers and even truckers typically haveon hand. This allows close monitoring of the shipment at multiple stagesduring shipment and upon receipt.

Having a certificate incorporated internally in the logger also is anadvantage in that loggers can be pre-certified en masse as operatingcorrectly, prior to use. Normally, loggers must be pre-certified bytesting them in a temperature controlled environment (a chamber) wherethe temperature is varied in a certain manner, and the logger is checkedto determine if the logger recorded the temperature changes accurately.With the certificate incorporated, a number of loggers can be testedtogether, and then the certificates can be read together to verifycorrect functioning. In a further improvement, the certificationreflects pre-programming which “knows” what the chamber temperaturevariation should be over time, and the certificate shows if thetemperature variation in the chamber does not match the expectedvalues—there is then a visible alert on the logger's certificate forthat logger.

In yet another embodiment, the logger is a slave where the data loggedcan be read and recorded (and if needed analyzed) by a master computer.One convenient form of this embodiment has a male USB on the loggerwhich plugs into the USB port on the computer. Preferably, as notedabove, the logger, retains pdf, excel, text and other formatsinternally. Thus, these documents can be read by computers, tablets,smart-phones and other hand-held or portable computing devices. Themaster-slave arrangement of loggers may be particularly preferred wheredifferent loggers are associated with different products in arefrigerator, freezer or climate-controlled condition during shipment.At selected intervals, one can take the data from the loggers to themaster-computer, preferably through the USB port. This arrangementeliminates the need for and the greater expense of real-time RFtransmission of time/temperature data (which further cannot be done forair cargo), as the monitoring at select intervals will be adequate toverify the reliability of the climate-control for each logger-associatedproduct.

Another preferred embodiment for loggers includes LCD displays which arecalled Epaper™ (by E Ink Holdings Inc., Taiwan). They can retain blackand white or color images (like bar codes, numerals, letters or Chinesecharacters) for extended periods (even years) with no power, and theyonly need the minimal power of an internal mini-battery as the energysupply to change the screen display. The certificate itself and/or a barcode or other product or logger identifiers can be displayed on LCDs onthe logger with this technology, and then read or reviewed by theoperator at a later time.

In a particular logger embodiment, the logger can be associated withenvironmental sensors (including temperature, humidity or others) usingcircuits printed on paper with nanotechnology, as disclosed in US Publ'nNo. 20110200873 (incorporated by reference). Such printed circuits wouldextend from a logger attached outside the box to the inside, or from alogger attached on the inside, out. The logger could also be embedded inthe box with the sensors extending from it. The sensors would feed databack to the logger for recordation or analysis. Such a system isdepicted in FIG. 4, where the logger 30 has sensors (arrows) extendingto cargo 40.

Shipment Systems

An issue related to preservation of refrigerant is the initial selectionof a shipment system. In that regard, U.S. Pat. No. 8,375,730 has suchdescription and is incorporated by reference. This patent describes analgorithm for selection of a shipment system where expectedtemperatures, shipment duration and cost are considerations inselection. As noted, the preservation of the refrigerant is directlyrelated to the heat transfer properties of the shipment system, andgenerally, more costly systems are better insulated and preserverefrigerant for longer periods (under the same conditions).

Preferred refrigerants are dry ice, ice, frozen gel packs or phasechange material. Preferred phase change materials are 1-dodecanol and1-decanol, and a particularly preferred combination has 98% 1-dodecanol,1.5% myristyl alcohol and 0.5% 1-decanol, as disclosed in U.S. Pat. No.8,192,924 (incorporated by reference).

In one embodiment, both system selection and monitoring of the shipmentcan be performed from a remote location. Such remote monitoring can beaccomplished with either RF transmission of data or using one of thelogger systems where data is stored and recorded in the logger, and thenextracted using a computer or other reader (which results are fed to theremote location). In one modification of the method, the customer canperform the shipping system selection and/or shipment monitoringfunctions themselves, and then decide themselves whether to take actionto preserve the shipment while it is en route (i.e., they can decidewhether to move the shipment to a faster transportation mode, instructthe shipper to add refrigerant, or divert the shipment or move thesystem to a temperature-controlled environment).

To make a selection of an appropriate system, one may also need tomonitor and establish the effect the ambient temperature has on the ice,gel packs or phase change material in each type of container which canbe part of a system, over time. Alternatively, such effect can bederived from the heat transfer characteristics of the packaging and themelting time of the ice, gel packs or phase change material, and notverified by actual monitoring. A monitoring system which includes analarm system for temperature excursions can alert the shipper orrecipient that the phase change material or ice may be melted and needsto be checked. Again, action can be taken if needed or if the risk levelof cargo damage is too high.

Segmenting the time of exposure (FIG. 2) to environmental ambienttemperatures is particularly appropriate in cases where the ambienttemperatures are unregulated during shipment, like in a truck trailer,but where the system spends a substantial part of the trip in atemperature-controlled environment (warehouse or temperature-controlledcargo hold). Segmenting in these cases helps protect against the effectof exposure to the unregulated ambient temperatures, but helps avoidover-compensating for the temperature extreme(s) during this exposure,and changing system requirements or taking action where there is no needto.

The containers for the system can be any of a number of designs andmaterials, including expanded polystyrene and polyethylene. Containerscan also be multi-layered, one inside another, with one such arrangementshown in U.S. Pat. No. 7,849,708 (incorporated by reference), wherein aninner container includes a phase change material and the product, and anouter container includes gel packs. Various combinations of containers,gel packs, ice, dry ice and phase change materials are readily apparentto one skilled in the art. For example, one could have multiplecontainers layered within each other, with layers of differenttemperature-control agents in different quantities in differentcontainers.

Phase change materials are relatively expensive, and thus one seeks tominimize their use, and substitute ice, gel packs, dry ice or containerdesigns which add insulation, where feasible. Phase change materials arenot consumed in the cooling process, and can be re-frozen and usedagain. But a practical difficulty in re-use may be that the customerwill not return the phase change material they receive—meaning it mustbe expensed with the rest of the system, which the customer wouldusually retain.

The real-time shipment monitoring disclosed herein allows selection ofslower, lower-cost shipment options. The cost of the faster shipmentoptions can be balanced against the likelihood that the system canmaintain the product for the time required under slower shipment modes.Shipment cost may be lower when using slower shipment with monitoring,to protect the cargo even with such slow shipment.

At some point following arrival of blood/biological materials at theend-user destination, the materials would be tested to determine theirsuitability for use in patients or as reagents in assays or otherwisetested to determine their suitability for the purpose they wererequested by the end-user. The effect of shipment on the products mightbe determined soon after arrival, or, their suitability for use inpatients or as reagents may be tested well after arrival. In eithercase, a biological assay is performed on the products, which can be oneor more of: an antibody-mediated assay including an enzyme-linkedimmunosorbent assay (See e.g., U.S. Pat. No. 8,021,850, incorporated byreference), a nucleic acid hybridization assay (See e.g., U.S. Pat. No.8,036,835, incorporated by reference), an elongation-mediated chainterminating assay (U.S. Pat. No. 6,972,174 incorporated by reference),an elongation-mediated assay or a ligation assay (U.S. Pat. No.7,262,032, incorporated by reference), a cell-based assay (U.S. Pat. No.7,655,421, incorporated by reference) or a viability, blood-typing ortissue-type matching assay, including but not limited to an HLA-typingor a serological assay.

The specific methods and compositions described herein arerepresentative of preferred embodiments and are exemplary and notintended as limitations on the scope of the invention. Other objects,aspects, and embodiments will occur to those skilled in the art uponconsideration of this specification, and are encompassed within thespirit of the invention as defined by the scope of the claims. It willbe readily apparent to one skilled in the art that varying substitutionsand modifications may be made to the invention disclosed herein withoutdeparting from the scope and spirit of the invention. The inventionillustratively described herein suitably may be practiced in the absenceof any element or elements, or limitation or limitations, which is notspecifically disclosed herein as essential. Thus, for example, in eachinstance herein, in embodiments or examples of the present invention,any of the terms “comprising”, “including”, containing”, etc. are to beread expansively and without limitation. The methods and processesillustratively described herein suitably may be practiced in differingorders of steps, and that they are not necessarily restricted to theorders of steps indicated herein or in the claims. It is also noted thatas used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural reference, and the plural include singularforms, unless the context clearly dictates otherwise. Under nocircumstances may the patent be interpreted to be limited to thespecific examples or embodiments or methods specifically disclosedherein. Under no circumstances may the patent be interpreted to belimited by any statement made by any Examiner or any other official oremployee of the Patent and Trademark Office unless such statement isspecifically and without qualification or reservation expressly adoptedin a responsive writing by Applicants. The invention has been describedbroadly and generically herein. Each of the narrower species andsubgeneric groupings falling within the generic disclosure also formpart of the invention. The terms and expressions that have been employedare used as terms of description and not of limitation, and there is nointent in the use of such terms and expressions to exclude anyequivalent of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention as claimed. Thus, it will be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those skilled inthe art, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the appended claims.

What is claimed is:
 1. A process of determining, at a point duringshipment, whether a solid phase refrigerant in a shipment container issufficient to preserve a shipment cargo, which is blood,pharmaceuticals, organs or other biological products, for a remainingshipment period to an intended recipient, comprising: monitoringtemperatures encountered and the time of exposure to such temperaturesto said point by the shipment, using a logger which is connected to aplurality of sensors; determining a likelihood that the remainingrefrigerant can maintain the shipment cargo within a specifiedtemperature range during the remaining shipment period based on anestimation of the temperatures likely to be encountered and the time ofexposure to said temperatures; and if risk that the remainingrefrigerant cannot maintain the shipment cargo within said range duringthe remaining shipment period is above a cut-off level, then addingrefrigerant to the shipment, moving the shipment to a fastertransportation mode, moving the shipment to a temperature-controlledenvironment, or diverting the shipment to a different recipient.
 2. Theprocess of claim 1 wherein the temperature-controlled environment is arefrigeration unit or a refrigerated cargo hold in a train, airplane ortruck.
 3. The process of claim 1 wherein the logger is connected withthe sensors using circuits printed on paper.
 4. The process of claim 1wherein the printed circuits extend from the logger which is outside theshipment container to the inside of the shipment container, or from thelogger which is inside the shipment container to the outside of theshipment container.
 5. The process of claim 1 wherein the sensors alsodetect relative humidity, pressure and CO₂ levels.
 6. The process ofclaim 1 wherein the solid phase refrigerant is dry ice, ice, frozen gelpacks, phase change material, 1-decanol or 1-dodecanol.
 7. The processof claim 1 further including a GPS or other geo-location system to allowlocation of the shipment en route.
 8. A process of determining, at apoint during shipment, whether a solid phase refrigerant in a shipmentcontainer is sufficient to preserve a shipment cargo, which is blood,pharmaceuticals, organs or other biological products, for a remainingshipment period to an intended recipient, comprising: monitoringtemperatures encountered and the time of exposure to such temperaturesto said point by the shipment, using a logger which is connected tosensors passing inside or outside the shipment container; determining alikelihood that the remaining refrigerant can maintain the shipmentcargo within a specified temperature range during the remaining shipmentperiod based on an estimation of the temperatures likely to beencountered and the time of exposure to said temperatures; and if riskthat the remaining refrigerant cannot maintain the shipment cargo withinsaid range during the remaining shipment period is above a specifiedlevel, then adding refrigerant to the shipment, moving the shipment to afaster transportation mode, moving the shipment to atemperature-controlled environment, or diverting the shipment to adifferent recipient.
 9. The process of claim 8 further includingdetermining the maximum predicted period of shipment for a biologicalproduct and the predicted ambient temperature ranges during shipment.10. The process of claim 8 further including selecting a system ofcontainers and solid phase refrigerants, likely to maintain thebiological products within a specified range of temperatures during theentire shipment period.
 11. The process of claim 8 further wherein thelogger records the temperatures and time of exposure in pdf, Excel ortext file format.
 12. The process of claim 8 wherein the logger recordof temperatures and time of exposure is stored in the format of acertificate acceptable to a regulatory agency including the FDA or WHOor standard-setting body including the NTIS.
 13. The process of claim 8further including downloading the recorded temperatures and time ofexposure from the logger to another device capable of reading the fileformat.
 14. The process of claim 8 wherein the temperature-controlledenvironment is a refrigeration unit or a refrigerated cargo hold in atrain, airplane or truck.
 15. The process of claim 8 wherein the loggeris connected with the sensors using circuits printed on paper.
 16. Theprocess of claim 8 wherein the printed circuits extend from the loggerwhich is outside the shipment container to the inside of the shipmentcontainer, or from the logger which is inside the shipment container tothe outside of the shipment container.
 17. The process of claim 8wherein the sensors also detect relative humidity, pressure and CO₂levels.
 18. The process of claim 1 wherein the solid phase refrigerantis dry ice, ice, frozen gel packs or phase change material.
 19. Theprocess of claim 18 wherein the phase change material is 1-decanol or1-dodecanol.
 20. The process of claim 8 further including a GPS or othergeo-location system to allow location of the shipment en route.